The increased proliferation of cultured neuroblastoma cells treated with vasoactive intestinal peptide is enhanced by simultaneous inhibition of neutral endopeptidase

Wollman, Yoram; Blumberg, Shmariahu; Spungin, Anya; Brenneman, Douglas E.; Fridkin, Mati; Wollman, Jonathan; Iaina, Adrian; Gozes, Illana

doi:10.1016/s0167-0115(02)00098-8

Cited by 8 publications

(9 citation statements)

References 20 publications

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“…Mutations in either of these respective transmitters show similar behavioural phenotypes (Aton et al, 2005;Lin et al, 2004), and these similarities are also evident at the receptor level (Harmar et al, 2002;Mertens et al, 2005). Our results show that PDF is a target of peptidase degradation, and while it remains unclear if this contributes to circadian functions, it is interesting to note that VIP has been found to be degraded by endopeptidases (neprilysin and kallikrein) (Gourlet et al, 1997;Kudo et al, 1998;Wollman et al, 2002) and that in the rat pineal, kallikrein displays a weak circadian rhythm that is antiphasic to VIP (Kudo et al, 1998).…”

Section: Pdf1-7 and Pdf8-18 Do Not Activate The Pdf Receptorsupporting

confidence: 64%

Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila

Isaac

Johnson

Audsley³

et al. 2007

Journal of Experimental Biology

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SUMMARY Recent studies have firmly established pigment dispersing factor (PDF), a C-terminally amidated octodecapeptide, as a key neurotransmitter regulating rhythmic circadian locomotory behaviours in adult Drosophila melanogaster. The mechanisms by which PDF functions as a circadian peptide transmitter are not fully understood, however; in particular, nothing is known about the role of extracellular peptidases in terminating PDF signalling at synapses. In this study we show that PDF is susceptible to hydrolysis by neprilysin, an endopeptidase that is enriched in synaptic membranes of mammals and insects. Neprilysin cleaves PDF at the internal Ser7–Leu8 peptide bond to generate PDF1-7 and PDF8-18. Neither of these fragments were able to increase intracellular cAMP levels in HEK293 cells cotransfected with the Drosophila PDF receptor cDNA and a firefly luciferase reporter gene, confirming that such cleavage results in PDF inactivation. The Ser7–Leu8 peptide bond was also the principal cleavage site when PDF was incubated with membranes prepared from heads of adult Drosophila. This endopeptidase activity was inhibited by the neprilysin inhibitors phosphoramidon (IC50, 0.15 μmol l–1) and thiorphan (IC50, 1.2 μmol l–1). We propose that cleavage by a member of the Drosophila neprilysin family of endopeptidases is the most likely mechanism for inactivating synaptic PDF and that neprilysin might have an important role in regulating PDF signals within circadian neural circuits.

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Section: Pdf1-7 and Pdf8-18 Do Not Activate The Pdf Receptorsupporting

confidence: 64%

Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila

Isaac

Johnson

Audsley³

et al. 2007

Journal of Experimental Biology

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“…VIP/PACAP stimulate growth/proliferation of NB-tumor-cells[157, 158] and induce differentiation and neuritogenesis[158, 159]. The neurotrophic-effects of PACAP on the NB-tumor-cell, SY5Y are mediaited by cAMP dependent processes involving Epac-dependent activation of ERK and activation of the p38 kinase[50].…”

Section: Vip/pacap: Neuroblastomasmentioning

confidence: 99%

Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

Moody¹,

Nuche-Berenguer

Jensen

2016

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review To summarize the roles of VIP/PACAP and their receptors(VPAC1, VPAC2/PAC1) in human tumors as well as their role in potential novel treatments. Recent findings Considerable progress has been made in understanding of the effects of VIP/PACAP on growth of various tumors as well as in the signaling cascades involved, especially of the role of transactivation of the Epidermal growth factor(EGF) family. The overexpression of VPAC1/2, PAC1 on a number of common neoplasms (breast, lung, prostate, CNS, neuroblastoma) is receiving increased attention both as a means of tumor imaging the location and extent of these tumors, as well as for targeted directed treatment, by coupling cytotoxic agents to VIP/PACAP analogues. Summary VIP/PACAP has prominent growth effects on a number of common neoplasms, which frequently overexpressed the three subtypes of their receptors. The increased understanding of their signaling cascades, effect on tumor growth/differentiation, and the use of the overexpression of these receptors for localization/targeted cytotoxic delivery, are all suggesting possible novel tumor treatments.

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“…a–f), which may be even further decreased in patients characterized by late AA. Interestingly, patients with AA have increased expression of neutral endopeptidase, a key VIP‐degrading enzyme . If additional analyses confirm the hypothesis that AA is associated with relative insensitivity to VIP stimulation due to reduced VPAC expression, irrespective of whether this is a primary (constitutive) or secondary (inflammation‐induced) phenomenon, this will render VPAC‐mediated signalling an even more promising therapeutic target for future AA management.…”

Section: Discussionmentioning

confidence: 93%

“…Interestingly, patients with AA have increased expression of neutral endopeptidase, 47 a key VIP-degrading enzyme. 48 If additional analyses confirm the hypothesis that AA is associated with relative insensitivity to VIP stimulation due to reduced VPAC expression, irrespective of whether this is a primary (constitutive) or secondary (inflammation-induced) phenomenon, this will render VPAC-mediated signalling an even more promising therapeutic target for future AA management. Indeed, decreased VPAC1/2 expression was previously described also in other autoimmune diseases, 36 suggesting that defects in the VIP receptor and signalling system may be a predisposing factor for the development of autoimmune conditions.…”

Section: Discussionmentioning

confidence: 98%

Vasoactive intestinal peptide, whose receptor-mediated signalling may be defective in alopecia areata, provides protection from hair follicle immune privilege collapse

et al. 2016

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Summary Background Alopecia areata (AA) is an autoimmune disorder whose pathogenesis involves the collapse of the relative immune privilege (IP) of the hair follicle (HF). Given that vasoactive intestinal peptide (VIP) is an immunoinhibitory neuropeptide released by perifollicular sensory nerve fibres, which play a role in IP maintenance, it may modulate human HF‐IP and thus be therapeutically relevant for AA. Objectives To answer the following questions: Do human HFs express VIP receptors, and does their stimulation protect from or restore experimentally induced HF‐IP collapse? Is VIP signalling defective in AA HFs? Methods Firstly, VIP and VIP receptor (VPAC1, VPAC2) expression in human scalp HFs and AA skin was assessed. In HF organ culture, we then explored whether VIP treatment can restore and/or protect from interferon‐γ‐induced HF‐IP collapse, assessing the expression of the key IP markers by quantitative (immuno‐)histomorphometry. Results Here we provide the first evidence that VIP receptors are expressed in the epithelium of healthy human HFs at the gene and protein level. Furthermore, VIP receptor protein expression, but not VIP+ nerve fibres, is significantly downregulated in lesional hair bulbs of patients with AA, suggesting defects in VIP receptor‐mediated signalling. Moreover, we show that VIP protects the HF from experimentally induced IP collapse in vitro, but does not fully restore it once collapsed. Conclusions These pilot data suggest that insufficient VIP receptor‐mediated signalling may contribute to impairing HF‐IP in patients with AA, and that VIP is a promising candidate ‘HF‐IP guardian’ that may be therapeutically exploited to inhibit the progression of AA lesions.

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The increased proliferation of cultured neuroblastoma cells treated with vasoactive intestinal peptide is enhanced by simultaneous inhibition of neutral endopeptidase

Cited by 8 publications

References 20 publications

Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila

Metabolic inactivation of the circadian transmitter, pigment dispersing factor (PDF), by neprilysin-like peptidases in Drosophila

Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer

Vasoactive intestinal peptide, whose receptor-mediated signalling may be defective in alopecia areata, provides protection from hair follicle immune privilege collapse

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